Adenosine has been known since the early 1920's to have potent vasodilator activity. It is a local hormone released from most tissues in the body during stress, especially hypoxic and ischemic stress (see Olsson et al., Physiological Reviews, 70(3), 761-845, 1990). As such, adenosine and adenosine-releasing agents are now commonly used to simulate the stress condition for diagnostic purposes (see The Medical Letter, 33(853), 1991).
Thallium-201 myocardial perfusion imaging is currently the most common approach in the use of stress-simulating agents as a means of imaging the coronary vessels to obtain a diagnosis of coronary artery disease. This is effected by injection of the stress agent such as adenesine at a dose of about 1 mg/kg body weight, followed by injection of the radionuclide, thallium-201, and scanning with a rotating gamma counter to image the heart and generate a scintigraph (see McNulty, Cardiovascular Nursing, 28(4), 24-29, 1992).
The mechanism underlying thallium-201 myocardial perfusion imaging is as follows: adenosine acting on coronary adenosine receptors causes relaxation of the coronary arterioles, thereby increasing blood flow throughout the heart. This effect is short-lasting and at a dose of 1 mg/kg, adenosine does not dilate other peripheral blood vessels to produce substantial systemic hypotension. Diseased or otherwise blocked coronary vessels will not further dilate in response to adenosine and the subsequent flow of thallium-201 through the heart will be less in these regions of hypoperfusion relative to other more normal areas of the heart. The resulting image allows the diagnostitian to quantitate the amount and severity of the coronary perfusion defect. This analysis is of paramount importance in selecting any further course of therapy and intervention by the physician [See U.S. Pat. Nos. 5,070,877 (Mohiuddin et al.) and 4,824,660 (Angello et al.)].
The use of adenosine and like-acting analogs is associated with certain side-effects. Adenosine acts on at least two subclasses of adenosine receptors, A.sub.1 or A.sub.2, both of which are found in the heart. The A.sub.1 receptor subtype, when activated by adenosine, among other actions, slows the frequency and conduction velocity of the electrical activity that initiates the heart beat. Sometimes adenosine, particularly at doses near 1 mg/kg, even blocks (stops) the heart beat during this diagnostic procedure--a highly undesirable action. The A.sub.2 receptor subtype is found in blood vessels and is further divided into A.sub.2a and A.sub.2b receptor subtypes (see Martin et al., Journal of Pharmacology and Experimental Therapeutics, 265(1), 248-253, 1993). It is the A.sub.2a receptor that is specifically responsible for mediating coronary vasodilation--the desired action of adenosine in the diagnostic procedure. Thus, the side-effects of adenosine and adenosine releasing agents result substantially from non-selective stimulation of the various adenosine receptor subtypes. Clearly, a better procedure would be to use a substance as a stress agent that selectively activates only the A.sub. 2a receptor, is short acting and works at doses substantially below 1 mg/kg body weight.
Certain 2-hydrazinoadenosine derivatives are known to display superior selectivity as coronary vasodilators (see U.S. patent application Ser. No. 873,440; Niiya et al., J. Med. Chem., 35, 4557-4561; and Ibid, 4562-4566, 1992). These substances are several thousand fold selective for the A.sub.2a adenosine receptor subtype. In addition to their selectivity, 2-hydrazinoadenosines are extremely potent. While this would seem an ideal combination for coronary dilation and diagnosis, the presence of A.sub.2a receptors on arterioles in other major vascular beds present a threat of severe systemic hypotension. It has now been discovered that these selective and potent derivatives of adenosine do not produce substantial systemic hypotension, are short acting, and appear to be more efficacious than adenosine in increasing coronary blood flow.